Helicobacter pylori 
A gram-negative spiral bacterium inhabits the gastric mucosa of humans, in which it may persist for a lifetime. The colonization of this unique ecological niche in approximately one-half of the human population makes it one of the most successful pathogens known to humankind. Enduring infection by H. pylori provokes active gastritis, alters gastric physiology, and may subsequently lead to peptic ulcer, atrophic gastritis, or even gastric adenocarcinoma. It is also recognized in the etiology of low-grade B-cell lymphoma.
H. pylori can be eradicated by the standard triple therapy comprised of a proton pump inhibitor and two antibiotic agents. The treatment of H. pylori infection using high-dosage antibiotics, however, has resulted in decreased efficacy. The infection proves to be difficult to cure; at least two high-dose antibiotics plus a proton pump inhibitor, twice daily for a 7- to 10-day period, is required to achieve high efficacy. Even more worrying, there is increasing emergence of resistant isolates that impede the cure rates, as seen for other bacteria including Mycobacterium tuberculosis. The development of novel drugs for resistant infections is thus needed for more effective control of these diseases in the future. Similarly, other resistant organisms including Staphylococcus aureus have become more and more difficult to cure. The need for new antibacterial therapies to overcome the problem of antibiotic resistance is therefore a major concern of healthcare professionals.
Current antibiotic agents are targeted towards a relatively small number of proteins, including cross-linking enzymes in the cell wall, ribosomal enzymes, and polymerases in DNA synthesis. One potential approach towards discovering new classes of inhibitors is to target crucial proteins in bacterial but not in mammals. The shikimate pathway, which involves seven sequential enzymatic steps in the conversion of erythrose 4-phosphate (E4P) and phosphoenolpyruvate (PEP) into chorismate for subsequent synthesis of aromatic compounds, is unique to microbial cells and parasites but absent in animals. Therefore, enzymes of this pathway are attractive targets for the development of nontoxic antimicrobial compounds, herbicides, and anti-parasitic agents. Indeed, the sixth-step enzyme, 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase, has been exploited as a target with glyphosate, a well-known herbicide.
Shikimate Pathway
The shikimate pathway (shows in FIG. 1) links metabolism of carbohydrates to biosynthesis of aromatic compounds. In a sequence of seven metabolic steps, phosphoenolpyruvate and erythrose 4-phosphate are converted to chorismate, the precursor of the aromatic amino acids and many aromatic secondary metabolites. All pathway intermediates can also be considered branch point compounds that may serve as substrates for other metabolic pathways. The shikimate pathway is an attractive target for the rational drug and herbicide design because it is essential in algae, higher plants, bacteria, and fungi, but absent from mammals.
In microorganisms, the shikimate pathway is used to synthesize three proteinogenic aromatic amino acids, that is, tryptophan, phenylalanine, and tyrosine; the folate coenzimes; benzoid and naphtoid quinones; and a broad range of mostly aromatic, secondary metabolies, including some siderophores. Although the shikimate pathway branches at points, chorismate is the last common branch point for the above-mentioned compounds. Five distinct enzymes to prephenate, anthranilate, aminodeoxychorismate, isochorismate, and p-hydroxybezoate, respectively convert from chorismate. These metabolites comprise the first committed intermediates in the biosynthesis of Phe, Tyr, Trp, folate, menaquinone and the siderophore enterobactin, and ubiquinone, respectively. The synthesis of these precursors is in most cases highly regulated.
In plants, thousands of primary and secondary aromatic compounds, which play a role in plant growth, development, and defense, are synthesized via the shikimate pathway. The flow through the shikimate pathway accounts for up to 20% of the photosynthetically fixed carbon in plants, most of which is shuttled through Phe and Tyr to generate abundant phenylpropanoid metabolites. The complexes demand for aromatic secondary metabolites in specific cell types and in response to multiple environmental stimuli suggests that regulation of Phe and Tyr biosynthesis in plants may differ fundamentally from regulation observed in microorganisms.
In microorganisms, the shikimate pathway is regulated by feedback inhibition and by repression of the first enzyme 3deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS). In higher plants, no physiological feedback inhibitor has been identified, suggesting that pathway regulation may occur exclusively at the genetic level. This difference between microorganisms and plants is reflected in the unusually large variation in the primary structures of the respective first enzymes. Several of the pathway enzymes occur in isoenzymic forms whose expression varies with environmental condition changes and, within the plant, from organ to organ.
Knowledge of the three-dimensional structures of the enzymes will undoubtedly aid the design of useful inhibitors, which may be used as a bactericide against M. tuberculosis, Xylella fastidiosa and others. The present invention provides a new method to inhibit the growth of H. pylori, wherein several inhibitors works on enzymes of the shikimate pathway.